Locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer both have a poor prognosis with five year survival rates ranging between 5-20%. The most common therapies include a combination of chemotherapy, radiation therapy, and when possible, surgery. However, given the poor outcomes, new complementary approaches which improve outcome are highly desirable. One promising and innovative complementary approach that potentially exploits fundamental metabolic differences between cancer cells and normal cells is the ketogenic diet (KD). Ketogenic diets are relatively non-toxic and have been used safely for years as a treatment for epilepsy. Ketogenic diets contain a high proportion of fat relative to protein and carbohydrates and result in elevated blood ketone levels and a lower glycemic index which force cells to rely more heavily on mitochondrial respiration, as opposed to glycolysis, for energy production. Cancer cells, relative to normal cells, have increased glucose uptake and are believed to exist in a state of chronic metabolic oxidative stress. It has been proposed, with significant supporting data, that cancer cells utilize increased glucose metabolism to generate reducing equivalents that are necessary to facilitate the decomposition of hydroperoxides as an adaptive response to metabolic oxidative stress caused by cancer cell specific dysfunctional mitochondrial O2 metabolism. If ketogenic diets limit glucose metabolism and force cells to derive energy from mitochondrial metabolism, it is reasonable to propose that these diets will also selectively enhance oxidative stress in cancer cells (relative to normal cells). The overarching hypothesis is that ketogenic diets (KD) will be clinically well tolerated and selectively enhance responses of non-small cell lung cancer (NSCLC) and pancreatic cancer to chemo-radio- sensitization via an oxidative stress mechanism. This is based on preliminary data in mice with human NSCLC or pancreas cancer xenografts fed KD during radiotherapy demonstrate enhanced therapeutic responses and increases in parameters indicative of oxidative stress with no evidence of adverse effects. To translate these exciting preclinical observations into human trials the current proposal will determine the tolerance of subjects with locally advanced NSCLC and pancreatic cancer to a prolonged (6.5-7.5 week) KD while receiving concurrent standard chemo-radiation therapy. Furthermore, subject blood will be analyzed for evidence of increases in parameters indicative of ketosis (serum ketones and blood glucose) as well as parameters of oxidative stress (lipid peroxidation, DNA oxidation, and protein oxidation). Successful completion of these studies will confirm the ability of subjects to tolerate a KD with concurrent chemo-radiation as well as assess the impact of the diet on metabolism and indices of oxidative stress. Successful completion of this study will allow for future trials to assess the potential for a KD to be used as an adjuvant to cancer therapy with the potential of increasing the efficacy of standard therapies for NSCLC and pancreatic cancer. PUBLIC HEALTH RELEVANCE: The prognosis for patients receiving radio-chemo-therapy for the treatment of locally advanced NSCLC and pancreatic cancer remains poor;therefore, easily implemented, relatively non-toxic dietary interventions that show promise to improve outcome are highly desirable. Furthermore, ketogenic diets show promise for exploiting inherent oxidative metabolic differences between cancer cells and normal cells to improve standard therapeutic outcomes. Thus, the development of a ketogenic diet, as a complementary adjuvant to standard therapy, could have a significant influence on improving standard cancer care.